Molecular basis for the GABAA receptor-mediated tonic inhibition in rat somatosensory cortex
Molecular basis for the GABAA receptor-mediated tonic inhibition in rat somatosensory cortex
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DOI：
10.1093/cercor/bhl087
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发表时间：
2007-08-01
期刊：
影响因子：
3.7
通讯作者：
Fukuda, Atsuo
中科院分区：
文献类型：
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作者：
Yamada, Junko;Furukawa, Tomonori;Fukuda, Atsuo
快速抑制性突触传递主要由作用于突触后GABA（A）受体的突触释放的γ-氨基丁酸（GABA）介导。GABA作用于GABA（A）受体，通过持续激活突触外受体，不仅产生阶段性抑制，而且产生强直性抑制。然而，在neoconex紧张性抑制的机制特征还没有得到很好的理解。为了解决这个问题，我们研究了大鼠脑片新皮质锥体神经元中药理学分离的GABA（A）受体介导的电流。荷包牡丹碱的浴应用阻断了微型抑制性突触后电流（mIPSC），并产生了一个向外移动的基线保持电流（I-hold）。低浓度的SR95531（一种竞争性GABA（A）受体拮抗剂）可消除mIPSC，但对I-hold无显著影响。苯二氮卓咪达唑仑通过增强紧张性GABA（A）受体介导的电流，使I-hold内移，V层神经元的电流显著大于II/III层神经元。单细胞逆转录-聚合酶链反应（RT-PCR）显示，第V层神经元α 1和α 5亚单位mRNA表达相对较高。L-655708，α 5亚基特异性反向激动剂，减少紧张性电流在第V层，但不是在第II/III层神经元，而唑吡坦，α 1亚基激动剂，在两个层中发挥同等的作用。这些数据表明，α 1 GABA（A）受体亚单位通常参与新皮层锥体神经元的紧张性抑制，而α 5亚单位则专门参与V层神经元。
Fast inhibitory synaptic transmission is primarily mediated by synaptically released gamma-aminobutyric acid (GABA) acting on postsynaptic GABA(A) receptors. GABA acting on GABA(A) receptors produces not only phasic but also tonic inhibitions by persistent activation of extrasynaptic receptors. However, the mechanistic characteristics of tonic inhibition in the neoconex are not well-understood. To address this, we studied pharmacologically isolated GABA(A) receptor-mediated currents in neocortical pyramidal neurons in rat brain slices. Bath application of bicuculline blocked miniature inhibitory postsynaptic currents (mIPSCs) and produced an outward shift in baseline holding current (I-hold). Low concentrations of SR95531, a competitive GABA(A) receptor antagonist, abolished mIPSCs but had no significant effect on I-hold. The benzodiazepine midazolam produced an inward shift in I-hold by augmenting tonic GABA(A) receptor-mediated currents, which were significantly greater in layer V neurons than in layer II/III. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a relatively higher expressions of alpha 1 and alpha 5 subunit mRNA in layer V neurons. L-655708, an alpha 5 subunit-specific inverse agonist, reduced tonic currents in layer V but not in layer II/III neurons, whereas zolpidem, an alpha 1-subunit agonist, exerted equivalent effects in both layers. These data suggest that the alpha 1 GABA(A) receptor subunit is generally involved in tonic inhibition in pyramidal neurons of the neocortex, whereas the alpha 5 subunit is specifically involved in layer V neurons.